Chromosomes store genetic information for living organisms and are essential for eukaryotic cell differentiation and function. Generally, chromosomes consist of one linear DNA molecule complexed with numerous proteins which are responsible for organizing the DNA into conformations suitable for gene replication and transcription. These conformations change at various stages of cell differentiation and are maintained and regulated by histones and nonhistone proteins.
Histones are small, basic proteins with molecular masses ranging from 11 kDa to 22 kDa. They are evolutionally conserved in sequence and structure across species which emphasizes their critical role in gene structure. Five types of histones, termed H1, H2A, H2B, H3, and H4, exist in a variety of forms due to post-translational modifications of certain side chains. A common feature of histones is their high content of positively charged side chains, about one in four residues is either lysine or arginine. When a histone-DNA complex forms, the positive charges of the histone side chains neutralize the negative charges of chromosomal DNA. Specifically, H2A, H2B, H3, and H4, as well as nonhistone proteins, interact with repeats of 200 base pairs of chromosomal DNA to form nucleosomes. Then, H2A interacts with H1 to group the nucleosomes into second order structure. Higher-order structures of chromosomes involve the interaction of histones and chromosomal DNA with a series of nonhistone proteins.
Nonhistone proteins are important in assembling nucleosomes and providing a structural scaffold for chromosomal DNA. Nucleoplasmin and N1 protein are nonhistone proteins which bind H2A/H2B and H3/H4, respectively, for assembly of nucleosomes. Topoisomerase II is a nonhistone protein responsible for cleaving and resealing double-stranded DNA in the process of scaffolding chromatin fiber into chromosomes.
Histone and nonhistone structures also form linkages, the functional aspect of which is largely unknown. Post-translational ubiquitination of histones H2A and H2B and CENP-A, an unusual form of histone H3 localized to centromeric heterochromatin, provides examples of the histone-nonhistone linkages (Goldknopf, I. L. and Bush, H. (1977) Proc. Natl. Acad. Sci. U.S.A. 74:864-868; Palmer, D. K. et al. (1991) Proc. Natl. Acad. Sci. U.S.A. 88:3734-3738). mH2A, identified in rat liver nucleosomes, is another histone-nonhistone fusion protein which contains a core histone and a large nonhistone region (Pehrson, J. R. and Fried, V. A. (1992) Science 257:1398-1400). The amino terminus of mH2A resembles full-length H2A, and the nonhistone region contains a leucine zipper-like motif and a basic domain rich in Lys and Arg (Pehrson and Fried, supra).
The discovery of a novel H2A-like protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of disorders associated with cell proliferation and inflammation.